Addictions constitute the most costly medical illnesses in society today. Onset of drug addiction often begins in adolescence and an improved understanding of the neural correlates of addiction vulnerability within this developmental period has significant implications for prevention and treatment interventions. Few prior investigations have followed at-risk cohorts from birth through adolescence, and many have focused on boys, generating a relative deficiency in our understanding of these processes in girls and in how boys and girls differ. No longitudinal studies to date have used brain imaging to identify how boys and girls at risk for addiction differ in brain function. Furthermore, although cocaine and other drug exposure in utero remains a significant public health problem, no studies to date have examined the influence of such exposure upon human adolescent brain function or addiction vulnerability. We propose examining 120 adolescent girls and boys 13-15 years of age who have been followed since birth, and were either prenatally cocaine-exposed to (PCE) or non-drug exposed in utero (NDE) and are matched on important sociodemographic features that categorize them as particularly vulnerable to the development of addiction. We propose using fMRI to investigate gender differences in the neural correlates of stress-responsiveness using an fMRI paradigm that our group has developed and used in prior SCOR-supported research. Our prior SCOR research found that adult men and women differed in the neural responses to individualized stress, appetitive and neutral scripts within limbic or "emotion-related" brain regions including caudate, amygdala, hippocampus and anterior cingulate, and that these differences in activations were largely observed during the stress scripts. Furthermore, these responses were differentially altered by chronic cocaine abuse in men and women. We propose using this paradigm to examine: 1) sex differences in the neural correlates of stress-responses in these younger individuals at increased risk for addiction;2) sex differences in neural activations related to in- utero cocaine exposure;and, 3) the stress-related brain activity that is predictive of subsequent substance use behaviors in girls and boys and how they differ across sex group. Findings from this study will provide critical gender-specific data on brain correlates of stress responses in adolescent girls and boys and provide insights into the risk related neural pathways in adolescent addiction.